血小板在肝细胞癌发生发展中的作用

于潇; 武国兵; 张爱斌; 程晓龙; 刘敏; 胡泽楠; 郑亚; 王玉平; 陈兆峰

doi:10.3969/j.issn.1001-5256.2022.06.043

血小板在肝细胞癌发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2022.06.043

于潇^{1, 2},
武国兵^{1, 2},
张爱斌^{1, 2},
程晓龙^{1, 2},
刘敏²,
胡泽楠²,
郑亚²,
王玉平²,
陈兆峰^2, , ,

1.
兰州大学第一临床医学院，兰州 730000
2.
兰州大学第一医院消化科，甘肃省胃肠病重点实验室，兰州 730000

基金项目:

国家自然科学基金 (81960430);

甘肃省自然科学基金 (21JR1RA073);

兰州大学第一医院院内基金 (ldyyyn2018-38)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：于潇、张爱斌、武国兵、程晓龙负责文献查找、阅读及文章撰写；刘敏、胡泽楠、郑亚、王玉平、陈兆峰负责文章修改。

详细信息

通信作者:
陈兆峰，zhfchen@lzu.edu.cn

计量
- 文章访问数: 614
- HTML全文浏览量: 346
- PDF下载量: 135
- 被引次数: 0
出版历程
- 收稿日期: 2021-10-26
- 录用日期: 2021-11-28
- 出版日期: 2022-06-20

Role of platelets in the development and progression of hepatocellular carcinoma

Xiao YU^{1, 2},
Guobing WU^{1, 2},
Aibin ZHANG^{1, 2},
Xiaolong CHENG^{1, 2},
Min LIU²,
Zenan HU²,
Ya ZHENG²,
Yuping WANG²,
Zhaofeng CHEN^{2
, ,
,}

1.
The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China
2.
Department of Gastroenterology, The First Hospital of Lanzhou University, Key Laboratory of Gastrointestinal Diseases of Gansu Province, Lanzhou 730000, China

Research funding:

National Natural Science Foundation of China (81960430);

Natural Science Foundation of Gansu Province (21JR1RA073);

The Fund of First Hospital of Lan Zhou University (ldyyyn2018-38)

More Information

Corresponding author: CHEN Zhaofeng, zhfchen@lzu.edu.cn(ORCID: 0000-0003-2921-1111)

摘要

摘要: 肝细胞癌是常见的肿瘤相关死亡原因之一。在我国，其发病率和死亡率都很高。近年研究显示，血小板与肝细胞癌的发生密切相关。本文通过文献回顾，发现血小板不仅参与止血，还作用于肝细胞和肿瘤微环境，促进新生血管的形成以及作为一种细胞介质通过免疫应答等途径参与肝细胞癌的发生发展。此外，血小板及其衍生物可作为肝细胞癌的潜在治疗靶点。因此，抗血小板治疗有望成为一种新型辅助策略应用于肝细胞癌的防治，具有重要的临床意义。
- 癌, 肝细胞 /
- 血小板 /
- 肿瘤微环境 /
- 外泌体 /
- 分子靶向治疗
Abstract: Hepatocellular carcinoma is one of the common causes of tumor-related death, and it has high morbidity and mortality rates in China. Recent studies have shown that platelets are closely associated with the development of hepatocellular carcinoma. Literature review shows that platelets not only participate in hemostasis, but also act on liver cells and tumor microenvironment, promote the formation of new blood vessels, and participate in the development and progression of hepatocellular carcinoma as a cell mediator through immune response and other pathways. In addition, platelets and their derivatives can be used as potential therapeutic targets for hepatocellular carcinoma. Therefore, antiplatelet therapy is expected to become a new adjuvant strategy for the treatment of hepatocellular carcinoma, which has important clinical significance.
- Carcinoma, Hepatocellular /
- Blood Platelets /
- Tumor Microenvironment /
- Exosomes /
- Molecular Targeted Therapy

HTML全文

图 1 血小板与HCC的关系

注：LSEC，肝窦内皮细胞；HSC，肝星状细胞。

Figure 1. Relationship between platelets and hepatocellular carcinoma

下载: 全尺寸图片幻灯片

图 2 肿瘤微环境

注：TAF，肿瘤相关成纤维细胞。

Figure 2. Tumor microenvironment

下载: 全尺寸图片幻灯片

图 3 血小板与肿瘤微环境相互作用促进HCC进展

Figure 3. Interaction between platelets and tumor microenvironment promotes the progression of hepatocellular carcinoma

下载: 全尺寸图片幻灯片

参考文献(45)

[1]	GARRIDO A, DJOUDER N. Cirrhosis: A questioned risk factor for hepatocellular carcinoma[J]. Trends Cancer, 2021, 7(1): 29-36. DOI: 10.1016/j.trecan.2020.08.005.
[2]	YAGI S, HIRATA M, MIYACHI Y, et al. Liver regeneration after hepatectomy and partial liver transplantation[J]. Int J Mol Sci, 2020, 21(21): 8414. DOI: 10.3390/ijms21218414.
[3]	HAYASHI T, SHIBATA M, OE S, et al. Antiplatelet therapy improves the prognosis of patients with hepatocellular carcinoma[J]. Cancers (Basel), 2020, 12(11): 3215. DOI: 10.3390/cancers12113215.
[4]	WOJTUKIEWICZ MZ, SIERKO E, HEMPEL D, et al. Platelets and cancer angiogenesis nexus[J]. Cancer Metastasis Rev, 2017, 36(2): 249-262. DOI: 10.1007/s10555-017-9673-1.
[5]	PAVLOVIC N, RANI B, GERWINS P, et al. Platelets as key factors in hepatocellular carcinoma[J]. Cancers (Basel), 2019, 11(7): 1022. DOI: 10.3390/cancers11071022.
[6]	CHEN F, ZHUANG X, LIN L, et al. New horizons in tumor microenvironment biology: challenges and opportunities[J]. BMC Med, 2015, 13: 45. DOI: 10.1186/s12916-015-0278-7.
[7]	SHAN Z, JU C. Hepatic macrophages in liver injury[J]. Front Immunol, 2020, 11: 322. DOI: 10.3389/fimmu.2020.00322.
[8]	POISSON J, LEMOINNE S, BOULANGER C, et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases[J]. J Hepatol, 2017, 66(1): 212-227. DOI: 10.1016/j.jhep.2016.07.009.
[9]	GARRIDO A, DJOUDER N. Cirrhosis: A questioned risk factor for hepatocellular carcinoma[J]. Trends Cancer, 2021, 7(1): 29-36. DOI: 10.1016/j.trecan.2020.08.005.
[10]	WAN S, ZHAO E, KRYCZEK I, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells[J]. Gastroenterology, 2014, 147(6): 1393-1404. DOI: 10.1053/j.gastro.2014.08.039.
[11]	TSUCHIDA T, FRIEDMAN SL. Mechanisms of hepatic stellate cell activation[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(7): 397-411. DOI: 10.1038/nrgastro.2017.38.
[12]	DHAR D, BAGLIERI J, KISSELEVA T, et al. Mechanisms of liver fibrosis and its role in liver cancer[J]. Exp Biol Med (Maywood), 2020, 245(2): 96-108. DOI: 10.1177/1535370219898141.
[13]	WANG H, LU Z, ZHAO X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer[J]. J Hematol Oncol, 2019, 12(1): 133. DOI: 10.1186/s13045-019-0806-6.
[14]	PROVOST P. The clinical significance of platelet microparticle-associated microRNAs[J]. Clin Chem Lab Med, 2017, 55(5): 657-666. DOI: 10.1515/cclm-2016-0895.
[15]	WANG H, LU Z, ZHAO X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer[J]. J Hematol Oncol, 2019, 12(1): 133. DOI: 10.1186/s13045-019-0806-6.
[16]	PAGGETTI J, HADERK F, SEIFFERT M, et al. Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts[J]. Blood, 2015, 126(9): 1106-1117. DOI: 10.1182/blood-2014-12-618025.
[17]	KIM JH, LEE CH, LEE SW. Exosomal transmission of microRNA from HCV replicating cells stimulates transdifferentiation in hepatic stellate cells[J]. Mol Ther Nucleic Acids, 2019, 14: 483-497. DOI: 10.1016/j.omtn.2019.01.006.
[18]	ZHOU Y, REN H, DAI B, et al. Hepatocellular carcinoma-derived exosomal miRNA-21 contributes to tumor progression by converting hepatocyte stellate cells to cancer-associated fibroblasts[J]. J Exp Clin Cancer Res, 2018, 37(1): 324. DOI: 10.1186/s13046-018-0965-2.
[19]	LIN W, WANG H, ZHONG M, et al. Effect and molecular mechanisms of jiedu recipe on hypoxia-induced angiogenesis after transcatheter arterial chemoembolization in hepatocellular carcinoma[J]. Evid Based Complement Alternat Med, 2021, 2021: 6529376. DOI: 10.1155/2021/6529376.
[20]	CHEN Q, XU L, CHEN J, et al. Tumor vasculature normalization by orally fed erlotinib to modulate the tumor microenvironment for enhanced cancer nanomedicine and immunotherapy[J]. Biomaterials, 2017, 148: 69-80. DOI: 10.1016/j.biomaterials.2017.09.021.
[21]	LI S, ZHANG Y, WANG J, et al. Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours[J]. Nat Biomed Eng, 2017, 1(8): 667-679. DOI: 10.1038/s41551-017-0115-8.
[22]	HEINDRYCKX F, GERWINS P. Targeting the tumor stroma in hepatocellular carcinoma[J]. World J Hepatol, 2015, 7(2): 165-176. DOI: 10.4254/wjh.v7.i2.165.
[23]	de PALMA M, BIZIATO D, PETROVA TV. Microenvironmental regulation of tumour angiogenesis[J]. Nat Rev Cancer, 2017, 17(8): 457-474. DOI: 10.1038/nrc.2017.51.
[24]	GORDON-WEEKS AN, LIM SY, YUZHALIN AE, et al. Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice[J]. Hepatology, 2017, 65(6): 1920-1935. DOI: 10.1002/hep.29088.
[25]	DEPPERMANN C, KUBES P. Platelets and infection[J]. Semin Immunol, 2016, 28(6): 536-545. DOI: 10.1016/j.smim.2016.10.005.
[26]	GHAFOORY S, VARSHNEY R, ROBISON T, et al. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury[J]. Blood Adv, 2018, 2(5): 470-480. DOI: 10.1182/bloodadvances.2017010868.
[27]	JIANG X, WANG J, DENG X, et al. The role of microenvironment in tumor angiogenesis[J]. J Exp Clin Cancer Res, 2020, 39(1): 204. DOI: 10.1186/s13046-020-01709-5.
[28]	KIKUCHI A, SINGH S, PODDAR M, et al. Hepatic stellate cell-specific platelet-derived growth factor receptor-α loss reduces fibrosis and promotes repair after hepatocellular injury[J]. Am J Pathol, 2020, 190(10): 2080-2094. DOI: 10.1016/j.ajpath.2020.06.006.
[29]	ORR MT, LANIER LL. Natural killer cell education and tolerance[J]. Cell, 2010, 142(6): 847-856. DOI: 10.1016/j.cell.2010.08.031.
[30]	KUROKAWA T, OHKOHCHI N. Platelets in liver disease, cancer and regeneration[J]. World J Gastroenterol, 2017, 23(18): 3228-3239. DOI: 10.3748/wjg.v23.i18.3228.
[31]	BEST MG, WURDINGER T. Tumor-educated platelets for the earlier detection of hepatocellular carcinoma[J]. Clin Res Hepatol Gastroenterol, 2020, 44(6): 794-795. DOI: 10.1016/j.clinre.2020.03.028.
[32]	VOLZ J, MAMMADOVA-BACH E, GIL-PULIDO J, et al. Inhibition of platelet GPVI induces intratumor hemorrhage and increases efficacy of chemotherapy in mice[J]. Blood, 2019, 133(25): 2696-2706. DOI: 10.1182/blood.2018877043.
[33]	PAPA AL, JIANG A, KORIN N, et al. Platelet decoys inhibit thrombosis and prevent metastatic tumor formation in preclinical models[J]. Sci Transl Med, 2019, 11(479). DOI: 10.1126/scitranslmed.aau5898.
[34]	MALEHMIR M, PFISTER D, GALLAGE S, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer[J]. Nat Med, 2019, 25(4): 641-655. DOI: 10.1038/s41591-019-0379-5.
[35]	KAPS L, SCHUPPAN D. Targeting cancer associated fibroblasts in liver fibrosis and liver cancer using nanocarriers[J]. Cells, 2020, 9(9): 2027. DOI: 10.3390/cells9092027.
[36]	SCHUPPAN D, KIM YO. Evolving therapies for liver fibrosis[J]. J Clin Invest, 2013, 123(5): 1887-1901. DOI: 10.1172/JCI66028.
[37]	WANG H, WU Q, LIU Z, et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma[J]. Cell Death Dis, 2014, 5(4): e1155. DOI: 10.1038/cddis.2014.122.
[38]	KARSDAL MA, NIELSEN SH, LEEMING DJ, et al. The good and the bad collagens of fibrosis-Their role in signaling and organ function[J]. Adv Drug Deliv Rev, 2017, 121: 43-56. DOI: 10.1016/j.addr.2017.07.014.
[39]	OUYANG JZ, ZHOU YZ, ZHU RL, et al. Application of combined therapy with molecular-targeted drugs and immune checkpoint inhibitors and other combined therapies in hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37(4): 925-930. DOI: 10.3969/j.issn.1001-5256.2021.04.043. 欧阳敬中, 周艳召, 朱瑞利, 等. 分子靶向药物与免疫抑制剂联合治疗及其他联合治疗在肝细胞癌中的应用[J]. 临床肝胆病杂志, 2021, 37(4): 925-930. DOI: 10.3969/j.issn.1001-5256.2021.04.043.
[40]	WINKLER M, STANICZEK T, KVRSCHNER SW, et al. Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling[J]. J Hepatol, 2021, 74(2): 380-393. DOI: 10.1016/j.jhep.2020.08.033.
[41]	POISSON J, LEMOINNE S, BOULANGER C, et al. Liver sinusoidal endothelial cells: Physiology and role in liver diseases[J]. J Hepatol, 2017, 66(1): 212-227. DOI: 10.1016/j.jhep.2016.07.009.
[42]	BREITKOPF-HEINLEIN K, MEYER C, KÖNIG C, et al. BMP-9 interferes with liver regeneration and promotes liver fibrosis[J]. Gut, 2017, 66(5): 939-954. DOI: 10.1136/gutjnl-2016-313314.
[43]	DESROCHES-CASTAN A, TILLET E, RICARD N, et al. Bone morphogenetic protein 9 is a paracrine factor controlling liver sinusoidal endothelial cell fenestration and protecting against hepatic fibrosis[J]. Hepatology, 2019, 70(4): 1392-1408. DOI: 10.1002/hep.30655.
[44]	GARCIA-TSAO G, KORZENIK JR, YOUNG L, et al. Liver disease in patients with hereditary hemorrhagic telangiectasia[J]. N Engl J Med, 2000, 343(13): 931-936. DOI: 10.1056/NEJM200009283431305.
[45]	JOHN M, KIM KJ, BAE S, et al. Role of BMP-9 in human liver disease[J]. Gut, 2019, 68(11): 2097-2100. DOI: 10.1136/gutjnl-2018-317543.